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| Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a death receptor ligand that has the ability to preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. TRAIL-based therapeutics, including recombinant TRAIL, TRAIL-receptor agonistic antibodies and TRAIL gene therapy, have now entered clinical trials. Although these therapeutics are promising, concerns regarding TRAIL resistance are causing research efforts to shift towards the identification of effective combination therapies. Small-molecule inhibitors, natural compounds, and drugs approved for treatment of diseases other than cancer have been shown to affect TRAIL receptors, antiapoptotic proteins and survival pathways in prostate, bladder and renal cell lines and in preclinical models. Changes in endogenous TRAIL and TRAIL receptor expression during the development of genitourinary malignancies and the way in which the expression pattern is affected by treatment are of great interest, and understanding the biological consequences of such changes will be important to maximize the potential of TRAIL-based therapeutics.